Y-ECCO Literature Review: Charles Miller

Methods

This was an observational multinational real-world study of adult IBD patients (aged greater than 18 years). Data was obtained from two US and one French nationwide healthcare database. Both anti-TNF-naïve and anti-TNF-experienced patients were included; prior exposure to other conventional biologics resulted in exclusion. Eligible patients were considered for inclusion if they commenced on VDZ after 1 January, 2014. Patients were followed up from the day of treatment initiation (cohort entry date) until outcome occurrence, death or up to week 16 in patients with UC and week 26 in patients with CD.

The combination therapy group was defined as starting VDZ with a concomitant exposure to thiopurines within 30 days of initiation. The monotherapy group was defined as not having thiopurine exposure 60 days prior to VDZ initiation.

For patients with CD the corticosteroid clinical-free remission (CFCR) endpoint was defined as a CD activity index (CDAI) of less than 150 points without systemic corticosteroid use, whilst for patients with UC the CFCR endpoint was a total Mayo score of 2 points or less (with no subscore exceeding 1) without systemic corticosteroid use.

The composite effectiveness outcome measure for treatment failure was based on hospitalisation or surgery relating to IBD, treatment switch to an alternate biologic or exposure to corticosteroid at week 16 (UC patients) or 26 (CD patients).

Treatment groups were propensity score matched (PSM) with 1:1 matching with a caliper of 0.02.

Key Findings

From a total of 10,299 vedolizumab users, after PSM 804 pairs of patients with CD and 1088 pairs of patients with UC were included in the analysis. There was prior anti-TNF exposure in 83.5% of patients with CD and 74.4% of patients with UC.

In patients with CD, week 26 treatment failure occurred in 236 (29.3%) on combination therapy and in 376 (34.3%) on monotherapy, with CD-related hospitalisation or surgery being the commonest reason for treatment failure. CD patients on combination therapy had a 15% reduced risk of treatment failure compared with CD patients on monotherapy (RR 0.85, 95% CI 0.74–0.98) at week 26. The trend was similar across all three databases as well as for secondary endpoints.

In patients with UC, week 16 treatment failure occurred in 236 (21.7%) on combination therapy and in 263 (24.2%) on monotherapy. The commonest reason for treatment failure was ongoing exposure to corticosteroids. The risk of treatment failure was similar between the two groups (RR 0.90, 95% CI 0.77–1.05) with similar findings across secondary endpoints.

Secondary analyses included assessment of risk of treatment failure in anti-TNF-experienced versus anti-TNF-naïve patients. The risk of treatment failure associated with combination therapy versus vedolizumab monotherapy appeared to be lower in anti-TNF-experienced (RR 0.90, 95% CI 0.77–1.05) compared with anti-TNF-naïve patients with CD (RR 1.26, 95% CI 0.71–2.25). For patients with UC, the risk of treatment failure in combination therapy versus monotherapy was similar in anti-TNF-experienced (RR 0.93, 95% CI 0.79–1.10) and anti-TNF-naïve patients (RR 0.98, 95% CI 0.65–1.46).

Additionally, rates of serious infections and hospitalisations unrelated to IBD did not differ between the two treatment groups for both patients with UC and those with CD.

Conclusion

This was a well-powered study with the use of three large population-based cohorts. It attempted to emulate randomised control trials (RCT), including SONIC [3], to assess the comparative effectiveness of VDZ monotherapy versus combination therapy with thiopurines in both UC and CD. No previous RCT had been designed to assess these treatment strategies. Using validated methodologies, the investigators demonstrated that risk of treatment failure was reduced at week 26 in CD patients on VDZ combination therapy with a thiopurine, but not in UC patients. In addition, in CD patients, a trend towards higher effectiveness of combination therapy in anti-TNF-experienced patients versus anti-TNF-naïve patients was demonstrated. The study has clear potential clinical applicability and addresses an important question.

In terms of limitations, hard endpoints such as endoscopic and histologic assessment were not included. Additionally, this study did not assess longer term outcomes.

The reason for incremental effectiveness of adding thiopurines to VDZ is yet to be understood. Data suggest that VDZ clearance may not be influenced by immunosuppressant addition and development of antidrug antibodies is rare [4]. The authors propose that this study should aid clinical decision making on the use of a concurrent thiopurine with VDZ. Further adequately powered RCTs are required to assess whether VDZ combination therapy with thiopurine results in better outcomes in UC and CD patients.

References

1. Yzet C, Diouf M, Singh S, et al. No benefit of concomitant immunomodulator therapy on efficacy of biologics that are not tumor necrosis factor antagonists in patients with inflammatory bowel diseases: a meta-analysis. Clin Gastroenterol Hepatol. 2021;19:668–79.
2. Hu A, Kotze PG, Burgevin A, et al. Combination therapy does not improve rate of clinical or endoscopic remission in patients with inflammatory bowel diseases treated with vedolizumab or ustekinumab. Clin Gastroenterol Hepatol. 2021;19:1366–76.
3. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010; 362:1383–95.
4. Rosario M, Dirks NL, Gastonguay MR, et al. Population pharmacokinetics- pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther. 2015;42:188–202.

Charles Miller - Short Biography

Charles Miller is a Gastroenterology Trainee at St Mary’s Hospital London. He has an interest in colonic motility in Ulcerative Colitis.